HIV keeps laughing. Time to change direction?

Dear Members of the Virology list,
Many recent articles in the scientific and popular press focus on
the discouraging prospects for a soon development of a vaccine
and/or cure for HIV. This reminds me of the old story about the
drunkard who looks for his keys close to the street lamp. The
reasoning that allowed recombinant-DNA genetic-analysis virology
to come to dominate HIV research and the search for anti-HIV
strategies was indeed as immediately "logical' as it would be
going to a lighted place to look for keys one just lost. This is
of course an a posteriori realization but not therefore one that
is deprived of teachings, especially now when it is quite certain
that the keys will not be found by the street lamp of HIV
research that is the very genetic analysis and recombinant DNA
instruments which had, at the onset of the AIDS crisis, already
allowed virologists to celebrate fascinating breakthroughs in
understanding the reductionistically approachable, one-gene-one-
function molecular biology of other viruses. HIV virologists set
out merrily to characterize HIV-specific structures and functions
since they reckoned that these could be targeted for disruption
without much damage to patients. This still sounds very nice and
beautiful but not that much if we remember that it ignored the
already-then well-known ability of RNA viruses to evolve very
quickly their one-gene-one-function features, and if we remind
ourselves that most of these features have to be targeted inside
infected cells by flooding these with the drug du jour, in an
open invitation for the drug to interact in undesirable ways with
the components of every cell, infected or not. More importantly,
other strategies to fight the virus were neglected simply because
they were not by the street light, i.e. because they involved
work that could not be tackled using recombinant-DNA genetic-
analysis tools. The basic epistemological flaw behind all of this
was thinking that understanding HIV was the best way to find out
how to neutralize HIV, a curious reasoning which if true would
lead us to conclude for instance that military hardware should be
inefficient since its design does not reflect a thorough
understanding of the mechanics of life. But the results have not
been that bad: anti-HIV drugs are keeping many people alive much
longer (when there is money to pay for treatment) which is a
marvelous achievement for patients but a meager one if one
considers the money and human labor that has been thrown at HIV
(the atomic bomb did not take twenty years to become
operational
). And neither should we forget the Sisyphian
struggle in which virologists have trapped themselves: they
develop a new drug over many years of painful toiling and then
helplessly see how the drug creates more or less serious side-
effects and how the virus evolves resistance to it after a few
weeks of exposure. This one-gene-one-function research program
has also led to a self-perpetuating tunnel vision of HIV: The
viral life cycle, for instance, is now often depicted using a
large cell within which multiple, fascinatingly complex processes
take place. Concededly, on one side of the depicted cell an HIV
virion is absorbed, and on the other new virions are released,
but this just stresses even more how the interior of the cell -
the playground of mainstream HIV virology - has become
everything, and how the HIV virion for instance whose nature
cannot be studied very well with recombinant-DNA genetic-analysis
tools, has become a peripheral non-entity. In the subdued but
very richly funded apotheosis of mainstream HIV research, HIV now
stands for "what HIV does within the cell, upon contact with the
cell, or when leaving the cell". So, it is not surprising that
nobody dares to ask the question "what should be done against HIV
and by whom", rather than the usual one "what can recombinant-DNA
genetic-analysis virology do against HIV". Asking the former
question would allow us to take a fresher look at HIV and AIDS,
ignoring the "requirement" that one look for anti-HIV strategies
that are compatible with the tools of mainstream HIV virology.
What should be done against HIV is quite simple: one needs a low-
toxicity treatment against which HIV cannot evolve resistance,
and an inexpensive one if possible. Identifying in this manner
which features of the HIV lifecycle should be targeted would then
tell us who could be in charge of finding ways to act on the
targets. The nucleus-encoded proteins that are packaged in the
HIV virion and the chemical and biophysical weak points of the
virion may offer untapped opportunities in this direction, but
non-surprisingly these features are chronically under-researched
(e.g. I could not find any papers in Medline on the pH and
osmolarity of the HIV virion's interior, and a few celebrity HIV
researchers I asked could not point out any either). Targeting
these features is very reasonable a priori: HIV could not evolve
resistance at all if the nucleus-encoded "virion's" proteins were
targeted, or only with great difficulty if one targeted chemical
or biophysical features of the virion whose evolutionary
modification requires large genetic-architectural changes rather
than a few of the same point mutations HIV has relied upon to
evolve resistance to every new drug developed so far. The
virion's markedly smaller size than that of cells and its not
being heavily coated, for instance, make it susceptible to be
damaged with dosages that should not affect cells to any
significant extent. And the virion's homeostatic helplessness
opens the possibility of fighting it with compounds whose damages
cells can repair but the virion cannot (compounds that besides
could be tried with robotized assays so that millions could be
screened in a very short time). It may or may not be time for the
HIV virion to become the focal point of HIV research but one
thing should be clear by now: The search for new anti-HIV drugs
should start by asking the right question, i.e. "what should be
done against HIV and by whom" and by remembering the right
answer: "find a low-toxicity, possibly inexpensive treatment HIV
cannot evolve resistance against". More drugs that target one-
gene-one-function viral features which can change easily via
point mutations, are not needed that badly anymore, and therefore
the powerful biomedical-industrial complex should start going
after a real cure, even if it requires giving up on the
profitable Sisyphian struggle HIV researchers have mired
themselves into.
by Dr. Marcos Antezana,
University of Chicago
mantezan at uchicago.edu
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